Quizartinib (AC220) is a highly potent second-generation Fms-like tyrosine kinase 3 (FLT3) inhibitor, with IC50 values of 1.1nM and 4.2nM for FLT3-ITD and FLT3-WT, respectively[1]. Quizartinib exhibits significantly higher selectivity for FLT3 than for other kinases such as PDGFRα, PDGFRβ, KIT, RET, and CSF-1R[2]. Quizartinib is primarily used to treat relapsed/refractory acute myeloid leukemia (AML), showing significant efficacy in patients with FLT3-ITD mutations[3]. Quizartinib can inhibit necroptosis by targeting receptor-interacting serine/threonine protein kinase 1 (RIPK1)[4].
In vitro, treatment of FLT3-ITD-mutant acute myeloid leukemia MV4-11 cells with Quizartinib (20nM) for 1h significantly inhibited cell growth and phosphorylation of FLT3 and ERK[5]. Treatment of neonatal rat ventricular myocytes and H9c2 cells with Quizartinib (200nM-20μM) for 72h dose-dependently reduced cell viability and significantly enhanced H2O2-induced cell death and apoptosis[6].
In vivo, oral administration of Quizartinib (1, 10mg/kg/day) for 14 days to mice bearing MV4-11 cell xenografts significantly inhibited tumor growth and reduced the levels of pFLT3, pErk1/2, pSTAT5, and pAkt in tumor cells[7].
References:
[1] Zarrinkar P P, Gunawardane R N, Cramer M D, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML)[J]. Blood, 2009, 114(14): 2984-2992.
[2] Acharya B, Saha D, Armstrong D, et al. FLT3 inhibitors for acute myeloid leukemia: successes, defeats, and emerging paradigms[J]. RSC Medicinal Chemistry, 2022, 13(7): 798-816.
[3] Wander S A, Levis M J, Fathi A T. The evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond[J]. Therapeutic advances in hematology, 2014, 5(3): 65-77.
[4] Aikawa T, Togashi N, Iwanaga K, et al. Quizartinib, a selective FLT3 inhibitor, maintains antileukemic activity in preclinical models of RAS-mediated midostaurin-resistant acute myeloid leukemia cells[J]. Oncotarget, 2020, 11(11): 943.
[5] Li M, Wei J, Zhu G, et al. Quizartinib inhibits necroptosis by targeting receptor‐interacting serine/threonine protein kinase 1[J]. The FASEB Journal, 2023, 37(10): e23178.
[6] Monogiou Belik D, Bernasconi R, Xu L, et al. The Flt3-inhibitor quizartinib augments apoptosis and promotes maladaptive remodeling after myocardial infarction in mice[J]. Apoptosis, 2024, 29(3): 357-371.
[7] Gunawardane R N, Nepomuceno R R, Rooks A M, et al. Transient exposure to quizartinib mediates sustained inhibition of FLT3 signaling while specifically inducing apoptosis in FLT3-activated leukemia cells[J]. Molecular cancer therapeutics, 2013, 12(4): 438-447.
Quizartinib (AC220)是一种高效的第二代Fms样酪氨酸激酶3（FLT3）抑制剂，对FLT3-ITD和FLT3-WT的IC50值分别为1.1nM和4.2nM[1]。Quizartinib对FLT3的选择性远高于PDGFRα、PDGFRβ、KIT、RET和CSF-1R等激酶[2]。Quizartinib主要用于治疗复发/难治性急性髓系白血病（AML），尤其对携带FLT3-ITD突变的患者显示出显著疗效[3]。Quizartinib能够通过靶向受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK1）抑制细胞坏死性凋亡[4]。
在体外，Quizartinib（20nM）处理FLT3-ITD突变急性髓系白血病MV4-11细胞1h，显著抑制了细胞生长，抑制了细胞内FLT3和ERK的磷酸化[5]。Quizartinib（200nM-20μM）处理新生大鼠心室肌细胞和H9c2细胞72h，剂量依赖性地降低了细胞的活力，显著增强了H2O2诱导的细胞死亡和凋亡[6]。
在体内，Quizartinib（1, 10mg/kg/day）通过口服治疗MV4-11细胞异种移植小鼠14天，显著抑制了小鼠体内肿瘤生长，降低了肿瘤细胞内pFLT3、pErk1/2、pSTAT5和pAkt的水平[7]。